CA2192155C - Process for the purification of (rr-ss)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts - Google Patents
Process for the purification of (rr-ss)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts Download PDFInfo
- Publication number
- CA2192155C CA2192155C CA002192155A CA2192155A CA2192155C CA 2192155 C CA2192155 C CA 2192155C CA 002192155 A CA002192155 A CA 002192155A CA 2192155 A CA2192155 A CA 2192155A CA 2192155 C CA2192155 C CA 2192155C
- Authority
- CA
- Canada
- Prior art keywords
- isomer
- mixture
- process according
- methoxyphenyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000000746 purification Methods 0.000 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 title claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- NLNQAKPOVVMNEG-UHFFFAOYSA-N 1-[2-(3-methoxyphenyl)cyclohex-2-en-1-yl]-n,n-dimethylmethanamine Chemical compound COC1=CC=CC(C=2C(CCCC=2)CN(C)C)=C1 NLNQAKPOVVMNEG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002955 isolation Methods 0.000 claims abstract description 4
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- 150000001412 amines Chemical class 0.000 claims abstract description 3
- 230000001376 precipitating effect Effects 0.000 claims abstract description 3
- 239000012264 purified product Substances 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- QDHLEFBSGUGHCL-UHFFFAOYSA-N 2-[(dimethylamino)methyl]cyclohexan-1-one Chemical compound CN(C)CC1CCCCC1=O QDHLEFBSGUGHCL-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- FBIKAGZLTPYSQW-UHFFFAOYSA-N 1-[2-(3-methoxyphenyl)cyclohexen-1-yl]-n,n-dimethylmethanamine Chemical compound COC1=CC=CC(C=2CCCCC=2CN(C)C)=C1 FBIKAGZLTPYSQW-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims 1
- MANBPLZDWGFQTP-UHFFFAOYSA-N 2-(dimethylamino)-1-(3-methoxyphenyl)cyclohexan-1-ol Chemical compound COC1=CC=CC(C2(O)C(CCCC2)N(C)C)=C1 MANBPLZDWGFQTP-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 238000001640 fractional crystallisation Methods 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 36
- 229960004380 tramadol Drugs 0.000 description 32
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000003747 Grignard reaction Methods 0.000 description 9
- 230000018044 dehydration Effects 0.000 description 6
- 238000006297 dehydration reaction Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- LTBLMYLXXFMMIY-UHFFFAOYSA-N 2-(diethylaminomethyl)cyclohexan-1-one Chemical compound CCN(CC)CC1CCCCC1=O LTBLMYLXXFMMIY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000857902 Bursera graveolens Species 0.000 description 1
- 206010012373 Depressed level of consciousness Diseases 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000149 liver necrosis Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL11628195A IL116281A (en) | 1995-12-07 | 1995-12-07 | Process for the purification of (rr,ss)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and its salts |
| IL116,281 | 1995-12-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2192155A1 CA2192155A1 (en) | 1997-06-08 |
| CA2192155C true CA2192155C (en) | 2005-06-14 |
Family
ID=11068279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002192155A Expired - Fee Related CA2192155C (en) | 1995-12-07 | 1996-12-05 | Process for the purification of (rr-ss)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5672755A (es) |
| EP (1) | EP0778262B1 (es) |
| AT (1) | ATE198879T1 (es) |
| AU (1) | AU713304B2 (es) |
| CA (1) | CA2192155C (es) |
| DE (1) | DE69611663T2 (es) |
| DK (1) | DK0778262T3 (es) |
| ES (1) | ES2154792T3 (es) |
| GR (1) | GR3035602T3 (es) |
| IL (1) | IL116281A (es) |
| PT (1) | PT778262E (es) |
| SK (1) | SK282179B6 (es) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL119121A (en) * | 1996-08-22 | 2000-11-21 | Chemagis Ltd | Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride |
| JP2001510180A (ja) | 1997-07-15 | 2001-07-31 | ラシンスキィ・リミテッド | トラマドール、その塩酸塩、及びそれらの製造方法 |
| US5877351A (en) * | 1997-12-24 | 1999-03-02 | Wyckoff Chemical Company, Inc. | Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts |
| IT1298597B1 (it) * | 1998-03-06 | 2000-01-12 | Secifarma Spa | Processo per la purificazione dell'(rr,ss)-2-(dimetilammino)metil- 1-(3-metossifenil)-cicloesanolo dall'(rs,sr)-2-(dimetilammino) |
| EP1077923B1 (en) * | 1998-05-22 | 2004-01-02 | Mallinckrodt Inc. | An improved synthesis and purification of (r*,r*)-2- (dimethylamino) methyl]-1-( 3-methoxyphenyl) cyclohexanol hydrochloride |
| ATE249432T1 (de) * | 1998-05-29 | 2003-09-15 | Upjohn Co | 3-((1'-n-methylamino)ethyl-n-benzyl)pyrrolidin- monomethanesulfonat |
| CA2375234A1 (en) * | 1999-06-22 | 2000-12-28 | Grunenthal Gmbh | Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol |
| GB0010437D0 (en) * | 2000-04-28 | 2000-06-14 | Darwin Discovery Ltd | Process |
| DE10108308A1 (de) * | 2001-02-21 | 2002-08-29 | Gruenenthal Gmbh | Verfahren zur Isolierung und Reinigung von (1RS,2RS)-2[(Dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol |
| US6649783B2 (en) | 2001-10-03 | 2003-11-18 | Euro-Celtique, S.A. | Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
| US6780891B2 (en) | 2001-11-30 | 2004-08-24 | Sepracor Inc. | Tramadol analogs and uses thereof |
| US8487002B2 (en) | 2002-10-25 | 2013-07-16 | Paladin Labs Inc. | Controlled-release compositions |
| TWI319713B (en) * | 2002-10-25 | 2010-01-21 | Sustained-release tramadol formulations with 24-hour efficacy | |
| US20060172006A1 (en) * | 2003-10-10 | 2006-08-03 | Vincent Lenaerts | Sustained-release tramadol formulations with 24-hour clinical efficacy |
| DE102005031041A1 (de) * | 2005-07-02 | 2007-01-04 | Palitzsch, Peter | Verfahren zur Isomerisierung von Tramadol |
| DK1940467T3 (da) | 2005-09-09 | 2017-02-13 | Paladin Labs Inc | Lægemiddelsammensætning med langvarig frigivelse |
| CN101252932B (zh) * | 2005-09-09 | 2012-10-03 | 安吉利尼莱博法姆有限责任公司 | 用于一天给药一次的曲唑酮组合物 |
| EP1785412A1 (en) * | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1219503B (de) | 1960-08-20 | 1966-06-23 | Firth Cleveland Ltd | Heiz- und/oder Kuehlgeraet |
| US3652589A (en) * | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
| US3653589A (en) | 1970-07-27 | 1972-04-04 | Carrier Corp | Air conditioning system |
| IL103096A (en) * | 1992-09-08 | 1996-12-05 | Chemagis Ltd | Process for purification 2 -]) Dimethylamino (methyl-1-) 3-methoxycinyl (cyclohexanol and its salts. |
-
1995
- 1995-12-07 IL IL11628195A patent/IL116281A/xx not_active IP Right Cessation
-
1996
- 1996-11-14 US US08/746,575 patent/US5672755A/en not_active Expired - Lifetime
- 1996-11-19 AT AT96308347T patent/ATE198879T1/de not_active IP Right Cessation
- 1996-11-19 DE DE69611663T patent/DE69611663T2/de not_active Expired - Lifetime
- 1996-11-19 AU AU71818/96A patent/AU713304B2/en not_active Ceased
- 1996-11-19 ES ES96308347T patent/ES2154792T3/es not_active Expired - Lifetime
- 1996-11-19 DK DK96308347T patent/DK0778262T3/da active
- 1996-11-19 EP EP96308347A patent/EP0778262B1/en not_active Expired - Lifetime
- 1996-11-19 PT PT96308347T patent/PT778262E/pt unknown
- 1996-11-22 SK SK1503-96A patent/SK282179B6/sk unknown
- 1996-12-05 CA CA002192155A patent/CA2192155C/en not_active Expired - Fee Related
-
2001
- 2001-03-20 GR GR20010400448T patent/GR3035602T3/el not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU7181896A (en) | 1997-06-12 |
| DK0778262T3 (da) | 2001-03-05 |
| SK150396A3 (en) | 1997-07-09 |
| EP0778262A2 (en) | 1997-06-11 |
| AU713304B2 (en) | 1999-11-25 |
| DE69611663D1 (de) | 2001-03-01 |
| ES2154792T3 (es) | 2001-04-16 |
| GR3035602T3 (en) | 2001-06-29 |
| ATE198879T1 (de) | 2001-02-15 |
| US5672755A (en) | 1997-09-30 |
| EP0778262A3 (en) | 1998-04-29 |
| PT778262E (pt) | 2001-05-31 |
| EP0778262B1 (en) | 2001-01-24 |
| IL116281A0 (en) | 1996-03-31 |
| IL116281A (en) | 1999-06-20 |
| DE69611663T2 (de) | 2001-06-13 |
| CA2192155A1 (en) | 1997-06-08 |
| SK282179B6 (sk) | 2001-11-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |